Benign prostatic hyperplasia (BPH) is a physiological disease common in middle-aged and elderly men. Along with the inevitable aging population, the incidence of BPH grows significantly than that in the past, and BPH has become one of the most common diseases of middle-aged and elderly men in China. Statistics show that prostate hyperplasia morbidity is very low before age 40, about half suffer from benign prostatic hyperplasia in men over the age of 50, and nearly 90% of 80-year-old males suffer from this disease. Benign prostatic hyperplasia is a benign adenomatous hyperplasia of prostatic urethra surrounding area cells, and the progressive enlargement of gland causes prostate urethra structure and causes urinary bladder outflow obstruction. Initial clinical manifestation is lower urinary tract symptoms (LUTS), and it eventually may develop into urinary retention, bladder infections, bladder stones and kidney failure, and even endangers patient's life. Therefore, benign prostatic hyperplasia, as one of common diseases in middle-aged and elderly men in China and abroad, greatly reduces life quality of patients.
The pathogenesis of benign prostatic hyperplasia is very complicated, and relates to various enzymes and receptors. Currently, two drugs most widely used for treatment of BPH in clinical are 5α-reductase inhibitors and α1-adrenergic receptors antagonists, whose treatment respectively aims at prostate volume and smooth muscle tension which are two factors causing symptoms of benign prostatic hyperplasia. The 5α-reductase inhibitors reduce prostate volume and improve dysuria through inhibiting conversion of testosterone to dihydrotestosterone in body, thereby reducing content of dihydrotestosterone in the prostate. But these drugs are only suitable for treating BPH patients with increased prostate volume and lower urinary tract symptom, and often are accompanied with erectile dysfunction, abnormal ejaculation, low libido and other side effects such as the feminization of male breast, breast pain etc. Thus, the most widely used drug in clinical is α1-adrenergic receptor antagonist.
Adrenergic receptors (ARs) are divided into α-receptors and β-receptors, and α-adrenergic receptors (α-ARs) are divided into two types of receptors, i.e., α1 and α2. Now three kinds of α1-receptor subtypes (α1A, α1B and α1D) have been identified. Research shows that α1 receptors mainly present in prostate matrix components and glandular epithelium, in which α1A-AR accounts for about 70% of total α1-ARs in human prostate and urinary system. In reproductive and urinary system, α1A-receptors are mainly distributed in the prostate, urethra and bladder trigone, and vas deferens; α1B-receptors are mainly distributed in blood vessels; and α1D-receptors are mainly distributed in detrusor of bladder and ureter smooth muscle.
In BPH pathological cases, α1-ARs density is significantly increased. Additionally, distribution of α1-ARs subtypes is different when age changes. The correlation between age and distribution is significant for understanding and treatment of benign prostatic hyperplasia and lower urinary tract symptoms, and for development of α1-adrenergic receptor antagonists. α1A-adrenergic receptor is considered to be an ideal target for treatment of benign prostatic hyperplasia, and blocking it has been proved to effectively reduce frequency of prostate smooth muscle contraction and improve bladder evacuation simultaneously. Blocking α1B-adrenergic receptor leads to vascular smooth muscle relaxation, arteriovenous expansion, peripheral resistance decrease and other symptoms, and may cause side effects such as dizziness and hypotension in some patients. Activating α1D-adrenergic receptor can lead to detrusor hyperactivity, and blocking it can reduce occurrence of evacuation symptoms as proven in animal experiments. Theoretically, α1A and α1D-adrenergic receptor dual inhibitors are very effective drugs for controlling benign prostatic hyperplasia, because it has two functions, i.e., reducing frequency of prostate smooth muscle contraction and inhibiting detrusor dysfunction, and, additionally, it can avoid cardiovascular side effects caused by α1B-adrenergic receptor blockade.
Phenoxybenzamine as the first generation of α receptor repressor is developed and utilized for effectively curing symptoms of benign prostatic hyperplasia. Phenoxybenzamine is an irreversible and non-selective α1/α2 receptor repressor and belongs to β-haloalkane, and it blocks α receptor in prostate and results in laxity of prostate fibrous tissue. Phenoxybenzamine is used in clinical to treat urination difficulty caused by non-mechanical urethra obstruction caused by prostate. Phenoxybenzamine contains β-chloroethylamine structure which easily reacts with other enzymes in body, thereby inducing toxicity and side effects. As a non-selective α-receptor repressor, phenoxybenzamine blocks α1-receptors and presynaptic α2 receptors, and causes feedback to the nerve endings to release norepinephrine, thereby inducing reflex tachycardia, arrhythmia and other side effects.
In order to reduce these side effects, the second generation of α1-adrenergic receptor antagonists are developed with a high selectivity for α1-receptor (such as: prazosin, terazosin, doxazosin, alfuzosin). α1-adrenergic receptor can alleviate prostate and urethra smooth muscle shrinkage caused by the sympathetic, and kinetically reduce symptoms of urethral obstruction. These drugs can effectively relieve lower urinary tract symptoms and reduce side effects caused by vasodilation. Prazosin drugs all have quinazoline nucleus structure, and are commonly used to treat lower urinary tract symptoms (LUTS) caused by BPH in clinical. However, due to widespread of α1-adrenergic receptor and important physiological functions, using α1-adrenergic receptor antagonists often lead to orthostatic hypotension, dizziness, weakness and other side effects.
In recent years, approved drugs for treating benign prostatic hyperplasia are α1A receptor selective antagonists tamsulosin and silodosin. Tamsulosin is considered as α1A-receptor selective antagonists, but it has poor selectivity to other α1-receptors, and due to an earlier time on the market, it has a large market share. But it still has some side effects, such as side effects on immunity system and ocular region. Additionally, it may causes ejaculation disorders, lower blood pressure, headaches and other side effects. The drug silodosin which entered into market recently has good receptor selectivity which is better than that of tamsulosin, and now its side effects in clinic are less than those of tamsulosin. Therefore, the drugs having good α1A-receptor selectivity undoubtedly has good market prospect for treating benign prostatic hyperplasia.